Mutations in Glycosyltransferases and Glycosidases: Implications for Associated Diseases.

Glycosylation, a crucial and the most common post-translational modification, coordinates a multitude of biological functions through the attachment of glycans to proteins and lipids. This process, predominantly governed by glycosyltransferases (GTs) and glycoside hydrolases (GHs), decides not only biomolecular functionality but also protein stability and solubility. Mutations in these enzymes have been implicated in a spectrum of diseases, prompting critical research into the structural and functional consequences of such genetic variations. This study compiles an extensive dataset from ClinVar and UniProt, providing a nuanced analysis of 2603 variants within 343 GT and GH genes. We conduct thorough MTR score analyses for the proteins with the most documented variants using MTR3D-AF2 via AlphaFold2 (AlphaFold v2.2.4) predicted protein structure, with the analyses indicating that pathogenic mutations frequently correlate with Beta Bridge secondary structures. Further, the calculation of the solvent accessibility score and variant visualisation show that pathogenic mutations exhibit reduced solvent accessibility, suggesting the mutated residues are likely buried and their localisation is within protein cores. We also find that pathogenic variants are often found proximal to active and binding sites, which may interfere with substrate interactions. We also incorporate computational predictions to assess the impact of these mutations on protein function, utilising tools such as mCSM to predict the destabilisation effect of variants. By identifying these critical regions that are prone to disease-associated mutations, our study opens avenues for designing small molecules or biologics that can modulate enzyme function or compensate for the loss of stability due to these mutations.

A novel synthetic method for backbone-cyclized polypeptide POL7080 with the help of hydrophobic-support materials.

Murepavadin (POL7080) in phase III clinical trials, a backbone-cyclized polypeptide composed of 14 amino acids, has a novel mode of action and shows a specific and efficient bactericidal effect against multidrug-resistant Pseudomonas aeruginosa. It is a potential candidate to treat severe P. aeruginosa infections in the future and still has significant commercial value for further research and development. In this paper, we report a liquid-phase peptide synthetic route for this valuable candidate polypeptide assisted by hydrophobic-support materials (tags), which overcomes the difficulties of high cost and poor yield in the traditional solid-phase synthesis of macrocyclic peptides. Through the careful optimization of reaction conditions and the innovative strategy of synthetic post-treatment, we established a simple and efficient liquid-phase synthetic route suitable for POL7080 and other similar structures, with satisfactory yield, high purity and a production process not being controlled by scale.

PD-L1 Blockade Peptide-Modified Polymeric Nanoparticles for Oxygen-Independent-Based Hypoxic Tumor Photo/Thermodynamic Immunotherapy.

Distant metastasis of malignant tumors is considered to be the main culprit for the failure of current antitumor treatments. Conventional single treatments often exhibit limited efficacy in inhibiting tumor metastasis. Therefore, there is a growing interest in developing collaborative antitumor strategies based on photothermal therapy (PTT) and free-radical-generated photodynamic therapy (PDT), especially utilizing oxygen-independent nanoplatforms, to address this challenge. Such antitumor strategies can enhance the therapeutic outcomes by ensuring the cytotoxicity of free radicals even in the hypoxic tumor microenvironment, thereby improving the effective suppression of primary tumors. Additionally, these approaches can stimulate the production of tumor-associated antigens and amplify the immunogenic cell death (ICD) effects, potentially feasible for enhancing the therapeutic outcomes of immunotherapy. Herein, we fabricated a functional nanosystem that co-loads IR780 and 2,2'-azobis[2-(2-imidazolin-2-yl)propane]-dihydrochloride (AIPH) to realize PTT-triggered thermodynamic combination therapy via the oxygen-independent pathway for the elimination of primary tumors. Furthermore, the nanocomposites were surface-decorated with a predesigned complex peptide (PLGVRGC-anti-PD-L1 peptide, MMP-sensitive), which facilitated the immunotherapy targeting distant tumors. Through the specific recognition of matrix metalloproteinase (MMP), the sensitive segment on the obtained aNC@IR780A was cleaved. As a result, the freed anti-PD-L1 peptide effectively blocked immune checkpoints, leading to the infiltration and activation of T cells (CTLs). This nanosystem was proven to be effective at inhibiting both primary tumors and distant tumors, providing a promising combination strategy for tumor PTT/TDT/immunotherapy.

Design and synthesis of benzochromene derivatives as AcrB inhibitors for the reversal of bacterial multidrug resistance.

A series of novel benzo[h]chromene compounds were designed, synthesized and evaluated for their biological activity as AcrB inhibitors. The compounds were assessed for their ability to potentiate the effect of antibiotics. Compounds with antibiotic-potentiating effects were then evaluated for inhibition of Nile Red efflux, and for off-target effects including activity on the outer and inner bacterial membranes and toxicity. Six compounds were identified to reduce the MIC values of at least one of the tested antibiotics by at least 4-fold, and further reduced the MICs in the presence of a membrane permeabilizer. The identified compounds were also able to inhibit Nile Red efflux at concentrations between 50 µM and 200 µM. The compounds did not disrupt the bacterial outer membrane nor display toxicity in a nematode model (Caenorhabditis elegans). The 4-methoxyphenoxy)propoxy derivative compound G6 possessed the most potent antibacterial potentiation with erythromycin by 8-fold even without the presence of a membrane permeabilizer. Furthermore, H6, G6, G10 and G11 completely abolished the Nile Red efflux at a concentration of 50 µM. The 3,4-dihydro-2H-benzo[h]chromen-5-yl)(morpholino)methanone core appears to be a promising chemical skeleton to be further studied in the discovery of more putative AcrB inhibitors.

Design, synthesis and evaluation of oxazolopyridinone derivatives as quorum sensing inhibitors.

The antibiotic crisis is associated with the appearance of multidrug resistant (MDR) pathogens, which has caused severe bacterial infections and imposed a huge burden on modern society. Therefore, there is an urgent need to develop new antibacterial drugs with novel mechanism of action. Here we designed and synthesized three series of benzoxazolone, oxazolopyridinone and 3-(2-hydroxyphenyl)hydantoin derivatives and evaluated their activity as novel quorum sensing (QS) inhibitors. We found that benzoxazolone and oxazolopyridinone derivatives had promising QS inhibitory activity in the minimum inhibitory concentration, pyocyanin and rhamnolipid inhibition assays. In particular, A10 and B20 at 256 µg/mL not only suppressed pyocyanin production regulated by QS in P. aeruginosa PAO1 by 36.55% and 46.90%, respectively, but also showed the strongest rhamnolipid inhibitory activity with the IC50 values of 66.35 and 56.75 µg/mL, respectively. Further studies demonstrated that B20 at 64 µg/mL inhibited biofilm formation in P. aeruginosa PAO1 by 40%, and weakened its swarming motility. More importantly, the bacterial mortality of B20 combined with ciprofloxacin and clarithromycin against P. aeruginosa were 48.27% and 49.79%, respectively, while ciprofloxacin and clarithromycin had only 16.99% and 29.11% of bacterial mortality against P. aeruginosa when used alone. Mechanistic studies indicated that B20 directly inhibited the QS pathway based on the GFP reporter strain assay. Overall, this compound with oxazolopyridinone core could serve as an antibacterial lead of QS inhibitor for further evaluation of its drug-likeness.

Enhanced photoelectrocatalytic performance for degradation of dimethyl phthalate over well-designed 3D hierarchical TiO2/Ti photoelectrode coupled dual heterojunctions.

A novel A/R-TiO2 NSs/NRs photoelectrode was constructed through electrodeposition of anatase TiO2 nanosheets (A-TiO2 NSs) with highly exposed {001} facet onto the 1D upright rutile TiO2 nanorods (R-TiO2 NRs). At first, A/R-TiO2 NSs/NRs exhibited enhanced adsorption of dimethyl phthalate (DMP) due to the specific recognition between Lewis acid sites of {001} facet and Lewis basic DMP. NH3-TPD and Py-IR revealed that the Lewis acidity on the {001} facet of A-TiO2 NSs was much stronger than that of R-TiO2 NRs, demonstrating superior adsorption capacity to DMP. DFT theoretical calculations coupled with in-situ ATR-FTIR spectra were performed to investigate the binding adsorption behavior of DMP on A/R-TiO2 NSs/NRs. Secondly, the rapid separation of excited charges and strong oxidation of h+ were achieved by the synergistic effect of dual heterojunctions (A/R "phase heterojunction" and {111}/{110} "facet heterojunction"). The A/R-TiO2 NSs/NRs exhibited 100% degradation efficiency for the target pollutant DMP within 3 h, whose rate constant (k) was 18.02 × 10-3 min-1, 2.16 times that of pure R-TiO2 NRs. In real wastewater application, A/R-TiO2 NSs/NRs achieved 93.8% elimination of DMP during 4 h and preserved excellent stability after 5 cycles, promising a wide-range of applications in water environment remediation.

Rational design and synthesis of Oreoch-2 analogues as efficient broad-spectrum antimicrobial peptides.

In recent years, bacterial resistance has risen sharply, which seriously endangers public health due to the abuse of antibiotics and the lack of new antibiotics. Therefore, there is an urgent need for new antimicrobial agents to combat multidrug-resistant (MDR) bacterial infections. In this paper, six Oreoch-2 analogues were rationally designed and efficiently synthesized by using the truncation strategy with Oreoch-2 as the lead compound. Evaluation of these analogues against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed. Among them, ZN-5 and ZN-6 were identified to be broad-spectrum effective analogues, which were superior to their parent peptide Oreoch-2. In addition, ZN-5 and ZN-6 had good stability to the physiological environment, and much higher selectivity to bacterial cells than to mammalian cells. Time-kill kinetics and transmission electron microscope (TEM) studies suggested that these analogues were typical bactericidal agents and quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. Moreover, ZN-5 and ZN-6 could inhibit biofilm formation of Staphylococcus aureus ATCC25923. Compared with their parent peptide Oreoch-2, ZN-5 and ZN-6 not only possessed shortened peptide chains, but also showed slightly improved antibacterial activity and greatly reduced hemolysis. This indicates that they are ideal lead compounds of antimicrobial peptides, which can be developed as substitutes for traditional antibiotics.

Recent Advances in the Development of Pyrazolopyridines as Anticancer Agents.

Cancer, especially malignant tumor, is a serious threat to people's life and health. It is recognized as an enormous challenge in the 21st century. Continuous efforts are needed to overcome this problem. Pyrazolopyridine nucleus, similar in structure to purine, shows a variety of biological activities, which is mainly attributed to the antagonistic nature towards the natural purines in many biological processes. This has aroused enormous attention for many researchers. At present, a large number of new chemical entities containing pyrazolopyridine nucleus have been found as anticancer agents. In this review we summarize novel pyrazolopyridine-containing derivatives with biological activities. Furthermore, we outline the relationships between the structures of variously modified pyrazolopyridines and their anticancer activity.

Serum metabolomic analysis in patients with Hashimoto's thyroiditis.

Background: Hashimoto's thyroiditis, an autoimmune thyroid disease, shows high morbidity worldwide, particularly in female. Patients with Hashimoto's thyroiditis have an increasing risk of hypothyroidism during the occurrence and progression of Hashimoto's thyroiditis. In recent years, metabolomics has been widely applied in autoimmune diseases, especially thyroid disorders. However, metabolites analysis in Hashimoto's thyroiditis is still absent. Methods: A total of 92 samples were collected, including 35 cases in the control group, 30 cases in the Hashimoto's thyroiditis with euthyroidism group, and 27 cases in the Hashimoto's thyroiditis with subclinical hypothyroidism group. SPSS 25.0 for statistical analysis and ROC curve, SIMCA 14.0, Metaboanalysis for multifactor analysis, and Origin 2021 for correlation analysis. Results: 21 metabolites were identified. 10 metabolites were obtained from control group versus HTE group, 8 serum metabolites were abnormal between control group and HTS group, 3 metabolites were derived from HTE group versus HTS. Kyoto Encyclopedia of Genes and Genomes Enrichment analysis showed that fatty acid degradation, Arginine, and proline metabolism have a significant impact on HTE, while lysine degradation, tyrosine metabolism play an important role HTS group, compared to control group. In the comparison between the HTE and HTS group, Valine, leucine, and isoleucine degradation and Valine, leucine, and isoleucine biosynthesis exists a key role. Correlation analysis shows clinical are not related to metabolites. ROC curve indicates SM, LPC, PC can efficiency in identification patients with HT in different clinical stage from healthy individuals. Conclusion: Serum metabolites were changed in HT. Phospholipids such as SM, LPC, PC influence the pathogenesis of Hashimoto's thyroiditis. Fatty acid degradation and lysine degradation pathways have an impact on different clinical stage of HT.

In situ construction of 3D TiO2 photoelectrode with multilevel facet heterojunctions towards the efficient removal of bisphenol A.

An innovative three-dimensional (3D) TiO2 photoelectrode with multilevel facet heterojunctions (FHs) is rationally designed based on in situ 1D rutile TiO2 nanorods with top {111} facets on a Ti mesh substrate. The 3D configuration composed of nanosheets and nanorods is provided with large specific area. The stepped band structure of the multilevel FH gives further impetus to spatial charge separation. The obtained FH-{111}TiO2/Ti photoelectrode achieves a 100% removal of bisphenol A (BPA) in only 20 min and presents an outstanding stability even after 10 cycles. Briefly, this work provides a reference pathway for the highly efficient removal of BPA.

Design, synthesis and evaluation of novel 9-arylalkyl-10-methylacridinium derivatives as highly potent FtsZ-targeting antibacterial agents.

With the increasing incidence of antibiotic resistance, new antibacterial agents having novel mechanisms of action hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Four novel series of substituted 9-arylalkyl-10-methylacridinium derivatives as FtsZ inhibitors were designed, synthesized and evaluated for their antibacterial activities against various Gram-positive and Gram-negative bacteria. The results demonstrated that they exhibited broad-spectrum activities with substantial efficacy against MRSA and VRE, which were superior or comparable to the berberine, sanguinarine, linezolid, ciprofloxacin and vancomycin. In particular, the most promising compound 15f showed rapid bactericidal properties, which avoid the emergence of drug resistance. However, 15f showed no inhibitory effect on Gram-negative bacteria but biofilm formation study gave possible answers. Further target identification and mechanistic studies revealed that 15f functioned as an effective FtsZ inhibitor to alter the dynamics of FtsZ self-polymerization, which resulted in termination of the cell division and caused cell death. Further cytotoxicity and animal studies demonstrated that 15f not only displayed efficacy in a murine model of bacteremia in vivo, but also no significant hemolysis to mammalian cells. Overall, this compound with novel skeleton could serve as an antibacterial lead of FtsZ inhibitor for further evaluation of drug-likeness.

EEG-Based Brain-Computer Interfaces (BCIs): A Survey of Recent Studies on Signal Sensing Technologies and Computational Intelligence Approaches and Their Applications.

Brain-Computer interfaces (BCIs) enhance the capability of human brain activities to interact with the environment. Recent advancements in technology and machine learning algorithms have increased interest in electroencephalographic (EEG)-based BCI applications. EEG-based intelligent BCI systems can facilitate continuous monitoring of fluctuations in human cognitive states under monotonous tasks, which is both beneficial for people in need of healthcare support and general researchers in different domain areas. In this review, we survey the recent literature on EEG signal sensing technologies and computational intelligence approaches in BCI applications, compensating for the gaps in the systematic summary of the past five years. Specifically, we first review the current status of BCI and signal sensing technologies for collecting reliable EEG signals. Then, we demonstrate state-of-the-art computational intelligence techniques, including fuzzy models and transfer learning in machine learning and deep learning algorithms, to detect, monitor, and maintain human cognitive states and task performance in prevalent applications. Finally, we present a couple of innovative BCI-inspired healthcare applications and discuss future research directions in EEG-based BCI research.

Efficient photocatalytic removal of phthalates easily implemented over a bi-functional {001}TiO2 surface.

It is stubborn to remove the lowly concentrated phthalic acid esters (PAEs) that usually coexist with other highly concentrated but low-toxic pollutants in municipal sewage. Herein, we report a novel strategy for completely removing the PAEs over a bi-functional {001}TiO2 surface (with highly exposed {001} facet), which not only serve as functional sites to specifically adsorb the target PAEs pollutants, but also contribute to an enhanced oxidation ability. The adsorption behavior of PAEs on {001}TiO2 is analyzed deeply through kinetic experiments combining with in situ ATR-FTIR spectroscopy and theoretical calculations. The results reveal that the adsorption capacities of PAEs on {001}TiO2 are about 4-5 times higher than that on TiO2, both of which follow the pseudo-second-order and Langmuir model. This is mainly attributed to the interfacial Lewis Acid-Base Pair between {001} facet Ti5c sites and CO of PAEs. Benefitting from the specific adsorption capability toward target pollutant and enhanced oxidation ability of {001} facets, nearly 100% of DMP or DEP in simulated wastewater can be eliminated by {001}TiO2 within 2 h illumination, and the relevant degradation rate constants (k) (3.67 h-1 for DMP and 2.19 h-1 for DEP) are 5.73 and 3.08 folds higher than that of pure TiO2, respectively. In the application of municipal wastewater, nearly 76% of DMP and 85% DEP can be eliminated by {001}TiO2 within 2 h illumination, which are nearly 3-6 fold higher than that of pure TiO2.

Photobiomodulation suppresses JNK3 by activation of ERK/MKP7 to attenuate AMPA receptor endocytosis in Alzheimer's disease.

Alzheimer's disease (AD), a severe age-related neurodegenerative disorder, lacks effective therapeutic methods at present. Physical approaches such as gamma frequency light flicker that can effectively reduce amyloid load have been reported recently. Our previous research showed that a physical method named photobiomodulation (PBM) therapy rescues Aß-induced dendritic atrophy in vitro. However, it remains to be further investigated the mechanism by which PBM affects AD-related multiple pathological features to improve learning and memory deficits. Here, we found that PBM attenuated Aß-induced synaptic dysfunction and neuronal death through MKP7-dependent suppression of JNK3, a brain-specific JNK isoform related to neurodegeneration. The results showed PBM-attenuated amyloid load, AMPA receptor endocytosis, dendrite injury, and inflammatory responses, thereby rescuing memory deficits in APP/PS1 mice. We noted JNK3 phosphorylation was dramatically decreased after PBM treatment in vivo and in vitro. Mechanistically, PBM activated ERK, which subsequently phosphorylated and stabilized MKP7, resulting in JNK3 inactivation. Furthermore, activation of ERK/MKP7 signaling by PBM increased the level of AMPA receptor subunit GluR 1 phosphorylation and attenuated AMPA receptor endocytosis in an AD pathological model. Collectively, these data demonstrated that PBM has potential therapeutic value in reducing multiple pathological features associated with AD, which is achieved by regulating JNK3, thus providing a noninvasive, and drug-free therapeutic strategy to impede AD progression.

Total Synthesis of Semaglutide Based on a Soluble Hydrophobic-Support-Assisted Liquid-Phase Synthetic Method.

Considering the high cost of the production of semaglutide, which is currently the most promising antidiabetic drug especially for the treatment of type 2 diabetes mellitus, a new synthetic route of semaglutide production that possesses excellent yield and high purity is of vital importance. Herein, we reported a newly developed synthetic route of semaglutide that is simple and efficient, based on a soluble hydrophobic-support-assisted liquid-phase synthetic method by applying Alloc-chemistry to the synthesis of the main chain peptide and side chain peptide of semaglutide. With careful optimization of the reaction conditions and innovative strategy of post-synthetic treatments, the total yield and purity of the crude semaglutide was improved satisfactorily.

In situ growth of M-{001}TiO2/Ti photoelectrodes: synergetic dominant {001} facets and ratio-optimal surface junctions for the effective oxidation of environmental pollutants.

We report a novel {001}TiO2/Ti photoelectrode by directly constructing "mirror-like" TiO2 microspheres on a Ti foil substrate (M-{001}TiO2/Ti). It presents highly enhanced PEC oxidation capability of DMP wastewater, which is mainly attributed to the significant synergetic effects of high exposure of {001} facets and equivalent {001}/{101} facet junctions.

Direct Conversion of Human Urine Cells to Neurons by Small Molecules.

Transdifferentiation of other cell type into human neuronal cells (hNCs) provides a platform for neural disease modeling, drug screening and potential cell-based therapies. Among all of the cell donor sources, human urine cells (hUCs) are convenient to obtain without invasive harvest procedure. Here, we report a novel approach for the transdifferentiation of hUCs into hNCs. Our study demonstrated that a combination of seven small molecules (CAYTFVB) cocktail induced transdifferentiation of hUCs into hNCs. These chemical-induced neuronal cells (CiNCs) exhibited typical neuron-like morphology and expressed mature neuronal markers. The neuronal-like morphology revealed in day 1, and the Tuj1-positive CiNCs reached to about 58% in day 5 and 38.36% Tuj1+/MAP2+ double positive cells in day 12. Partial electrophysiological properties of CiNCs was obtained using patch clamp. Most of the CiNCs generated using our protocol were glutamatergic neuron populations, whereas motor neurons, GABAergic or dopaminergic neurons were merely detected. hUCs derived from different donors were converted into CiNCs in this work. This method may provide a feasible and noninvasive approach for reprogramming hNCs from hUCs for disease models and drug screening.

Recent progress on carbon nanomaterials for the electrochemical detection and removal of environmental pollutants.

Rapid global industrialization and explosive population growth have resulted in an increase in the discharge of harmful and toxic compounds. These toxic inorganic gases, volatile organic compounds, heavy metals, personal care products, endocrine-disrupting chemicals, dyes, and pharmaceuticals are destroying the balance in the Earth and increasing environmental toxicity at an alarming rate. Thus, their detection, adsorption and removal are of great significance. Various carbon nanomaterials including carbon nanotubes, graphene, mesoporous carbon, carbon dots, and boron-doped diamond have been extensively utilized and further proven to be ideal candidates for resolving environmental problems, emerging as adsorbents, electrochemical sensors and electrodes. Herein, we review the recent advances, progress and achievements in the design and properties of carbon nanomaterials and their applications for the electrochemical detection and removal of environmental pollutants.

Noninvasive estimation of assist pressure for direct mechanical ventricular actuation.

Direct mechanical ventricular actuation is effective to reestablish the ventricular function with non-blood contact. Due to the energy loss within the driveline of the direct cardiac compression device, it is necessary to acquire the accurate value of assist pressure acting on the heart surface. To avoid myocardial trauma induced by invasive sensors, the noninvasive estimation method is developed and the experimental device is designed to measure the sample data for fitting the estimation models. By examining the goodness of fit numerically and graphically, the polynomial model presents the best behavior among the four alternative models. Meanwhile, to verify the effect of the noninvasive estimation, the simplified lumped parameter model is utilized to calculate the pre-support and the post-support left ventricular pressure. Furthermore, by adjusting the driving pressure beyond the range of the sample data, the assist pressure is estimated with the similar waveform and the post-support left ventricular pressure approaches the value of the adult healthy heart, indicating the good generalization ability of the noninvasive estimation method.